This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. More than 200,000 people in the United States are diagnosed with a primary or metastatic brain tumor annually. The life expectancy for these individuals is approximately 9-12 months from the time of diagnosis. This poor prognosis is due to the ineffectiveness of existing therapies (e.g., chemotherapy and radiotherapy) against brain cancer, where the problem is the inability to differentiate cancer cells from healthy cells. Currently, there is no curative therapy for brain cancer. Thus, the field is in great need for cancer cell-selective therapies. This proposal outlines a target-specific approach to treating brain cancer that could lead to a curative therapy. Relative to healthy brain tissue, the heightened metabolism of brain cancer cells (e.g., malignant gliomas) increases their reliance the ion transport proteins, specifically sodium-proton (NHE) exchangers. The inhibition of these cell surface proteins disrupts the intricate pH and ion balances within ca ncer cells to a much greater extent than in normal cells, and this leads to glioma cell death. Consequently, NHE is an excellent molecular target for brain cancer therapy. We will synthesize potent inhibitors in a prodrug form. As the prodrugs encounter extracellular enzymes from gliomas at the tumor site, they will release inhibitors that bind to NHE to cause glioma death. These inhibitors also are expected to assist with the regional management of tumor swelling and increased intracranial pressure often associated with brain cancer. The proposed project seeks to demonstrate a prodrug approach for cell surface ion exchange inhibition as a selective therapy for brain cancer.